Autoinflammatory Syndrome: Diagnosis and Treatment Approach
Overview
Autoinflammatory syndromes require early recognition through genetic testing and clinical phenotyping, followed by IL-1 targeted therapy with a treat-to-target strategy aiming for complete remission defined as absence of clinical symptoms and CRP <5-10 mg/L. 1
Diagnostic Approach
Initial Clinical Recognition
The following clinical patterns should prompt consideration of specific autoinflammatory diseases:
CAPS (Cryopyrin-Associated Periodic Syndromes):
- Urticaria-like rash, cold/stress-triggered episodes, sensorineural hearing loss, chronic aseptic meningitis, skeletal abnormalities 1
- Fever, progressive hearing loss, headaches, early morning nausea/vomiting, musculoskeletal symptoms, conjunctivitis 1
TRAPS (TNF Receptor-Associated Periodic Syndrome):
- Long-lasting fever episodes (>7 days), migratory rash, periorbital edema, myalgia, positive family history 1
- Abdominal pain, chest pain, testicular pain 1
MKD (Mevalonate Kinase Deficiency):
- Age at onset <1 year, periodic fever lasting 4-6 days, gastrointestinal symptoms (severe abdominal pain, vomiting, diarrhea) 1
- Cervical lymphadenopathy, aphthous stomatitis, urticarial or maculopapular rash 1
- History of post-vaccination triggers 1
- Severe form (mevalonic aciduria) presents with cognitive impairment 1
DIRA (Deficiency of IL-1 Receptor Antagonist):
- Pustular psoriasis-like rashes with pathergy, osteomyelitis (CRMO-like disease, rib flaring, cloaking of femoral head, odontoid lesions) 1
- Nail changes (onychomadesis), absence of bacterial osteomyelitis 1
Mandatory Laboratory Workup
Inflammatory Markers (Every Visit):
- ESR, CRP, CBC with differential (assess for granulocytosis) 1
- S100 proteins and SAA where available 1
- CRP <5-10 mg/L indicates adequate inflammation control 1
Genetic Testing:
- Use next-generation sequencing (NGS) platform if available for comprehensive evaluation 1
- Sanger sequencing for targeted genes: NLRP3 (CAPS), TNFRSF1A (TRAPS), MVK (MKD), IL1RN (DIRA) 1
- Deep sequencing may be needed for CAPS and TRAPS to detect somatic mutations not identified by standard NGS 1
- For DIRA: chromosomal microarray analysis (CMA) if Sanger/WES/WGS negative, as large deletions in IL1RN may not be detected 1
Additional Screening:
- Urinalysis for proteinuria (AA amyloidosis screening) every 6-12 months 1
- Mevalonic acid in urine if MKD suspected 1
Disease-Specific Diagnostic Workup
CAPS:
- Audiogram and ophthalmologic examination (slit lamp, retinal evaluation) at baseline 1
- Lumbar puncture and head MRI if clinically indicated for aseptic meningitis 1
DIRA:
- X-ray of chest, upper and lower limbs 1
- MRI/CT of spine including odontoid to assess inflammatory bone involvement 1
- Dermatology consultation and skin biopsy (neutrophilic dermatosis with exocytosis and subcorneal pustules highly suggestive) 1
Critical Diagnostic Pitfalls
- Patients with low penetrance variants in NLRP3 or TNFRSF1A (e.g., R121Q) may present differently from "canonical" disease and have different treatment responses 1
- Exclude infectious, malignant, and other causes before diagnosing autoinflammatory syndromes 2, 3
- Refer patients without disease-causing mutations to specialty/research centers for further workup 1
Treatment Approach
Primary Treatment Goal
The ultimate goal is complete remission, defined as absence of clinical symptoms and normal inflammatory markers (CRP <5-10 mg/L). 1 If remission cannot be achieved, minimal disease activity is an acceptable alternative target. 1
FDA/EMA-Approved IL-1 Targeted Therapies
CAPS:
- Canakinumab: 2-8 mg/kg every 8 weeks (pediatric); 150-600 mg every 8 weeks (adults >40 kg) 1, 4
- Rilonacept: Loading dose 4.4 mg/kg weekly, maintenance 2.2 mg/kg weekly (pediatric); loading 320 mg weekly, maintenance 160 mg weekly (adults) 1
- Anakinra: 1-2 mg/kg/day (for MWS phenotype) 1
NOMID/CINCA:
- Anakinra: 1-8 mg/kg/day (first-line, FDA and EMA approved) 1
- Canakinumab: 2-8 mg/kg every 4 weeks (pediatric); 150-600 mg every 4 weeks (adults >40 kg) 1
TRAPS:
MKD:
DIRA:
- Anakinra: 1-8 mg/kg/day 1
- Rilonacept: 4.4 mg/kg weekly (pediatric); loading 320 mg weekly, maintenance 320 mg weekly (adults) 1
Dose Escalation Strategy
For patients with persistent disease activity (PGA ≥2 or CRP >10 mg/L without adequate reduction):
- Days 8-14: Additional dose if <40% CRP reduction from baseline 4
- Days 15-28: Additional dose if <70% CRP reduction from baseline 4
- After Day 29: Up-titrate to 300 mg (or 4 mg/kg) every 4 weeks if PGA ≥2 and CRP ≥30 mg/L 4
Treatment Principles
- IL-1 blocking therapies control inflammation without glucocorticoids 1
- Treatment must be administered continuously in most patients to maintain disease control 1
- Adjust dose/frequency based on disease activity and inflammatory marker normalization 1
- Avoid TNF inhibitor coadministration due to increased serious infection risk 4
Monitoring Strategy
Disease Activity Assessment (Every Visit)
Clinical Monitoring:
- Use Autoinflammatory Diseases Activity Index (AIDAI) for symptom tracking 1
- Physician Global Assessment (PGA) and Patient/Parent Global Assessment (PPGA) 1
- Monitor disease-specific symptoms per Table 5 guidelines 1
Laboratory Monitoring:
- ESR, CRP, CBC with differential, S100 proteins, SAA at each visit 1
- Assess for hepatosplenomegaly, lymphadenopathy, fatigue 1
Long-Term Monitoring:
- Urinalysis for proteinuria every 6-12 months (AA amyloidosis surveillance) 1
- Growth, bone mineral density, sexual development as indicated 1
- Autoinflammatory Disease Damage Index (ADDI) for damage assessment 1
Safety Monitoring
Infection Surveillance:
- Screen for tuberculosis (active and latent) before initiating therapy 4
- Avoid live vaccines during treatment 4
- Ensure pneumococcal and inactivated influenza vaccines are current before starting therapy 4
- Discontinue therapy if serious infection develops 4
Macrophage Activation Syndrome (MAS):
- Remain vigilant for infection or disease worsening as MAS triggers 4
- Eleven cases observed in 201 SJIA patients in clinical trials 4
Specialist Referral
Refer to rheumatology or specialty center if: